Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism

Summary Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using four ATR inhibitors including two in clinical testing. The response to pharmacological ATR inhibitors was compared with genetic systems to investigate the ATR dependence of the effects observed. The ATR inhibitor, VX-970, was found to lead to an accumulation of p62 and LC3-II indicative of a blocked autophagy. This increase in p62 occurred post-transcriptionally and in all the cell lines tested. However, our data indicate that the accumulation of p62 occurred in an ATR-independent manner and was instead an off-target response to the ATR inhibitor. This study has important implications for the clinical response to pharmacological ATR inhibition, which in some cases includes the blockage of autophagy.
Graphical Abstract
Highlights • Inhibition of ATR using VX-970 leads to an accumulation of p62 • VX-970-mediated accumulation of p62 occurs independently of ATR • VX-970-mediated accumulation of p62 is consistent with blocked autophagy
Biological Sciences; Biochemistry; Biochemical Mechanism; Cancer